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Study stopped prematurely to test a new formulation of Exendin (9-39)
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The primary aim of this study is to evaluate the effect of Exendin (9-39) on glucose requirements to maintain euglycemia in pediatric patients with congenital hyperinsulinism (CHI) who have failed medical therapy. The secondary aims are to determine the therapeutic plasma levels, plasma half-life and pharmacokinetics of Exendin (9-39) during a 9-hour intravenous infusion.
This study will enroll infants with congenital hyperinsulinism owing to KATP channel mutations who are unresponsive to medical therapy and will require a pancreatectomy to control hypoglycemia from a single academic medical center in the United States.
An open-label, two-period, two-treatment crossover study design with a dose-escalation component will be implemented. Successive cohorts of patients (up to 5 participants/cohort) will each receive a fixed dose of Exendin (9-39) infusion and normal saline vehicle on two separate days in random order. The protocol specifies 0.02 mg/kg/hr, via continuous intravenous infusion, administered over 9-hours for the first cohort. The volume of saline to be infused will be calculated to match the volume of Exendin (9-39). Successive cohorts will be given doses that are increased in up to 1/2 log increments. Overall, the investigators hypothesize that antagonism of the GLP-1 receptor by Exendin (9-39) will increase fasting blood glucose levels, prevent protein-induced hypoglycemia and decrease glucose requirement to maintain euglycemia in infants with CHI.
Aim 1. To examine the effect of Exendin (9-39) on glucose requirements to maintain euglycemia in infants with congenital hyperinsulinism unresponsive to medical therapy.
Aim 2. To determine therapeutic plasma levels, plasma half-life and pharmacokinetics of Exendin-(9-39) during an intravenous infusion.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Exendin (9-39) 0.02 mg/kg/hr | Experimental | Cohort 1: Participants will be administered 0.02 mg/kg/hr of Exendin (9-39) and vehicle (normal saline), via continuous intravenous infusion, over 9 hours on two separate days in random order, with 3 hours of follow-up after the last dose is administered or until blood glucose is < 70 mg/dL (whichever comes first). Glucose infusion rates (GIR) will be titrated three hours prior to infusions to keep blood glucose in the range of 70-90 mg/dL. During both infusions, blood glucose will be measured every 30 minutes. |
|
| Exendin (9-39) 0.04 mg/kg/hr | Experimental | Cohort 2: Participants will be administered 0.04 mg/kg/hr of Exendin (9-39) and vehicle (normal saline), via continuous intravenous infusion, over 9 hours on two separate days in random order, with 3 hours of follow-up after the last dose is administered or until blood glucose is < 70 mg/dL (whichever comes first). Glucose infusion rates (GIR) will be titrated three hours prior to infusions to keep blood glucose in the range of 70-90 mg/dL. During both infusions, blood glucose will be measured every 30 minutes. |
|
| Exendin (9-39) 0.10 mg/kg/hr | Experimental | Cohort 3: Participants will be administered 0.10 mg/kg/hr of Exendin (9-39) and vehicle (normal saline), via continuous intravenous infusion, over 6 hours on two separate days in random order, with 3 hours of follow-up after the last dose is administered or until blood glucose is < 70 mg/dL (whichever comes first). Glucose infusion rates (GIR) will be titrated three hours prior to infusions to keep blood glucose in the range of 70-90 mg/dL. During both infusions, blood glucose will be measured every 30 minutes. |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Exendin (9-39) | Drug | A short-term intravenous infusion of the investigational drug, Exendin (9-39), will be administered over up to 9 hours. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Mean Glucose Infusion Rate (GIR) | To assess the effect of Exendin (9-39) on glucose infusion rate, glucose infusion rate (GIR) over the last 2 hours of the treatment period was calculated by adding the total amount of intravenous glucose (mg) received over 2 hours divided by the weight (kg) and by time (120 min) during infusion of Exendin (9-39) and normal saline vehicle. | Up to 9 hours after the initiation of infusion |
| To Determine the Pharmacokinetics of Exendin (9-39) | The following PK variables of interest include AUC0-∞, AUC0-t, maximal concentration (Cmax), time to maximal concentration (Tmax), concentration at end of infusion (Ceoi), steady state volume of distribution (Vss), clearance (CL) and half-life (t1/2) of Exendin (9-39). These will be derived through both non-compartmental and model-based methods. | Up to 12 hours after the initiation of infusion |
| Measure | Description | Time Frame |
|---|---|---|
| Safety and Tolerability of Exendin (9-39) | Number of participants with adverse events as a measure of safety and tolerability [evaluated by the result of laboratory safety tests (hematology, chemistry, urinalysis), vital signs, physical examinations, and 12-lead ECG] | Up to 24 hours post-infusion |
| Mean Plasma Insulin |
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Inclusion Criteria:
Exclusion Criteria:
Evidence of a medical condition that might alter results, including kidney failure, severe liver dysfunction, severe respiratory or cardiac failure
Treatment with medications that may affect glucose metabolism at the time of initiation of study procedures, including:
Suspected Beckwith-Wiedemann syndrome or other syndromic forms of congenital hyperinsulinism.
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| Name | Affiliation | Role |
|---|---|---|
| Diva D De Leon, MD MSCE | Children's Hospital of Philadelphia | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| The Children's Hospital of Philadelphia | Philadelphia | Pennsylvania | 19104 | United States |
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Of the 14 enrolled participants, 13 met inclusion criteria and were randomized to treatment.
Participants were recruited based on a confirmed clinical diagnosis of congenital hyperinsulinism at 1 academic medical center between August 2009 and October 2019. The first participant was enrolled on August 26, 2008 and the last participant was enrolled in January 25, 2017.
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| ID | Title | Description |
|---|---|---|
| FG000 | Exendin (9-39) 0.02 mg/kg/hr | Cohort 1: Participants will be administered 0.02 mg/kg/hr of Exendin (9-39) and vehicle (normal saline), via continuous intravenous infusion, over 9 hours on two separate days in random order, with 3 hours of follow-up after the last dose is administered or until blood glucose is < 70 mg/dL (whichever comes first). Glucose infusion rates (GIR) will be titrated three hours prior to infusions to keep blood glucose in the range of 70-90 mg/dL. During both infusions, blood glucose will be measured every 30 minutes. |
| FG001 | Exendin (9-39) 0.04 mg/kg/hr | Cohort 2: Participants will be administered 0.04 mg/kg/hr of Exendin (9-39) and vehicle (normal saline), via continuous intravenous infusion, over 9 hours on two separate days in random order, with 3 hours of follow-up after the last dose is administered or until blood glucose is < 70 mg/dL (whichever comes first). Glucose infusion rates (GIR) will be titrated three hours prior to infusions to keep blood glucose in the range of 70-90 mg/dL. During both infusions, blood glucose will be measured every 30 minutes. |
| FG002 | Exendin (9-39) 0.10 mg/kg/hr | Cohort 3: Participants will be administered 0.10 mg/kg/hr of Exendin (9-39) and vehicle (normal saline), via continuous intravenous infusion, over 6 hours on two separate days in random order, with 3 hours of follow-up after the last dose is administered or until blood glucose is < 70 mg/dL (whichever comes first). Glucose infusion rates (GIR) will be titrated three hours prior to infusions to keep blood glucose in the range of 70-90 mg/dL. During both infusions, blood glucose will be measured every 30 minutes. |
| FG003 | Exendin (9-39) 0.20 mg/kg/hr | Cohort 4: Participants will be administered 0.20 mg/kg/hr of Exendin (9-39) and vehicle (normal saline), via continuous intravenous infusion, over 9 hours on two separate days in random order, with 3 hours of follow-up after the last dose is administered or until blood glucose is < 70 mg/dL (whichever comes first). Glucose infusion rates (GIR) will be titrated three hours prior to infusions to keep blood glucose in the range of 70-90 mg/dL. During both infusions, blood glucose will be measured every 30 minutes. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Cohort 1: Dose Level 1 |
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| Cohort 2: Dose Level 2 |
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| Cohort 3: Dose Level 3 |
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| Cohort 4: Dose Level 4 |
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| ID | Title | Description |
|---|---|---|
| BG000 | Exendin (9-39) 0.02 mg/kg/hr | Cohort 1: Participants will be administered 0.02 mg/kg/hr of Exendin (9-39) and vehicle (normal saline), via continuous intravenous infusion, over 9 hours on two separate days in random order, with 3 hours of follow-up after the last dose is administered or until blood glucose is < 70 mg/dL (whichever comes first). |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Mean Glucose Infusion Rate (GIR) | To assess the effect of Exendin (9-39) on glucose infusion rate, glucose infusion rate (GIR) over the last 2 hours of the treatment period was calculated by adding the total amount of intravenous glucose (mg) received over 2 hours divided by the weight (kg) and by time (120 min) during infusion of Exendin (9-39) and normal saline vehicle. | Subjects served as their own control for comparison between the effects of Exendin (9-39) and the normal saline vehicle. The trial was terminated after 14 participants enrolled in the study. No data is available for any outcome measures. | Posted | Up to 9 hours after the initiation of infusion |
|
Safety monitoring for adverse events will occur for 24-hours post study-drug infusion. For this study, the treatment follow-up period is defined by the half-life of the investigational product.
Safety population = all participants who received any dose of the investigational product. Subjects served as their own control for comparison between the effects of Exendin (9-39) and the normal saline vehicle.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Exendin (9-39) 0.02 mg/kg/hr | Cohort 1: Participants will be administered 0.02 mg/kg/hr of Exendin (9-39) and vehicle (normal saline), via continuous intravenous infusion, over 9 hours on two separate days in random order, with 3 hours of follow-up after the last dose is administered or until blood glucose is < 70 mg/dL (whichever comes first). |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Emesis | Gastrointestinal disorders | CTCAE (4.0) | Systematic Assessment |
The trial was terminated after 14 participants enrolled in the study. No data is available for any outcome measures.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Diva D. Deleon, MD,MSCE | The Children's Hospital of Philadelphia | 215-590-3420 | deleon@email.chop.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Apr 25, 2017 | Feb 25, 2020 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D044903 | Congenital Hyperinsulinism |
| D006946 | Hyperinsulinism |
| D007003 | Hypoglycemia |
| D008659 | Metabolic Diseases |
| D010182 | Pancreatic Diseases |
| D044882 | Glucose Metabolism Disorders |
| D007232 | Infant, Newborn, Diseases |
| ID | Term |
|---|---|
| D004066 | Digestive System Diseases |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D009750 | Nutritional and Metabolic Diseases |
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| ID | Term |
|---|---|
| C083773 | exendin (9-39) |
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This is a two-period, two-treatment cross-over clinical study with a dose-escalation component. Each subject, in random order, will receive an intravenous (IV) infusion of Exendin (9-39) and normal saline vehicle for up to 9 hours on two separate days.
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| Exendin (9-39) 0.20 mg/kg/hr | Experimental | Cohort 4: Participants will be administered 0.20 mg/kg/hr of Exendin (9-39) and vehicle (normal saline), via continuous intravenous infusion, over 9 hours on two separate days in random order, with 3 hours of follow-up after the last dose is administered or until blood glucose is < 70 mg/dL (whichever comes first). Glucose infusion rates (GIR) will be titrated three hours prior to infusions to keep blood glucose in the range of 70-90 mg/dL. During both infusions, blood glucose will be measured every 30 minutes. |
|
| Vehicle | Drug | A short-term intravenous infusion of normal saline (0.9% NaCl), or the vehicle, will be administered over up to 9 hours. |
|
|
To assess the effect of Exendin (9-39) on plasma insulin levels, samples were collected at various time points during the infusion [Exendin (9-39) or vehicle] including: at the start of the infusion (T=0) and at 1, 5, and 9 hours post initiation of the infusion. |
| Up to 9 hours after the initiation of infusion |
| Mean Plasma Glucose | To assess the effect of Exendin (9-39) on plasma glucose levels, samples were collected at various time points during the infusion [Exendin (9-39) or vehicle] including: at the start of the infusion (T=0) and at 1, 5, and 9 hours post initiation of the infusion. | Up to 9 hours after the initiation of infusion |
| Mean Betahydroxybutyrate Levels | To assess the effect of Exendin (9-39) on mean betahydroxybutyrate levels, samples were collected at various time points during the infusion [Exendin (9-39) or vehicle] including: at the start of the infusion (T=0) and hourly up to 12-hours post initiation of the infusion. | Up to 12 hours after the initiation of infusion |
| COMPLETED |
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| COMPLETED |
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| BG001 |
| Exendin (9-39) 0.04 mg/kg/hr |
Cohort 2: Participants will be administered 0.04 mg/kg/hr of Exendin (9-39) and vehicle (normal saline), via continuous intravenous infusion, over 9 hours on two separate days in random order, with 3 hours of follow-up after the last dose is administered or until blood glucose is < 70 mg/dL (whichever comes first). |
| BG002 | Exendin (9-39) 0.10 mg/kg/hr | Cohort 3: Participants will be administered 0.10 mg/kg/hr of Exendin (9-39) and vehicle (normal saline), via continuous intravenous infusion, over 6 hours on two separate days in random order, with 3 hours of follow-up after the last dose is administered or until blood glucose is < 70 mg/dL (whichever comes first). |
| BG003 | Exendin (9-39) 0.20 mg/kg/hr | Cohort 4: Participants will be administered 0.20 mg/kg/hr of Exendin (9-39) and vehicle (normal saline), via continuous intravenous infusion, over 9 hours on two separate days in random order, with 3 hours of follow-up after the last dose is administered or until blood glucose is < 70 mg/dL (whichever comes first). |
| BG004 | Total | Total of all reporting groups |
| Participants |
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| Sex: Female, Male | Count of Participants | Participants |
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| Ethnicity (NIH/OMB) | Count of Participants | Participants |
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| Race (NIH/OMB) | Count of Participants | Participants |
|
| OG001 | Exendin (9-39) 0.04 mg/kg/hr | Cohort 2: Participants will be administered 0.04 mg/kg/hr of Exendin (9-39) and vehicle (normal saline), via continuous intravenous infusion, over 9 hours on two separate days in random order, with 3 hours of follow-up after the last dose is administered or until blood glucose is < 70 mg/dL (whichever comes first). |
| OG002 | Exendin (9-39) 0.10 mg/kg/hr | Cohort 3: Participants will be administered 0.10 mg/kg/hr of Exendin (9-39) and vehicle (normal saline), via continuous intravenous infusion, over 6 hours on two separate days in random order, with 3 hours of follow-up after the last dose is administered or until blood glucose is < 70 mg/dL (whichever comes first). |
| OG003 | Exendin (9-39) 0.20 mg/kg/hr | Cohort 4: Participants will be administered 0.20 mg/kg/hr of Exendin (9-39) and vehicle (normal saline), via continuous intravenous infusion, over 9 hours on two separate days in random order, with 3 hours of follow-up after the last dose is administered or until blood glucose is < 70 mg/dL (whichever comes first). |
| OG004 | Vehicle | All participants will be administered normal saline vehicle, via continuous intravenous infusion, over up to 9 hours. Subjects served as their own control for comparison between the effects of Exendin (9-39) and the normal saline vehicle. |
|
| Primary | To Determine the Pharmacokinetics of Exendin (9-39) | The following PK variables of interest include AUC0-∞, AUC0-t, maximal concentration (Cmax), time to maximal concentration (Tmax), concentration at end of infusion (Ceoi), steady state volume of distribution (Vss), clearance (CL) and half-life (t1/2) of Exendin (9-39). These will be derived through both non-compartmental and model-based methods. | Subjects served as their own control for comparison between the effects of Exendin (9-39) and the normal saline vehicle. The trial was terminated after 14 participants enrolled in the study. No data is available for any outcome measures. | Posted | Up to 12 hours after the initiation of infusion |
|
|
| Secondary | Safety and Tolerability of Exendin (9-39) | Number of participants with adverse events as a measure of safety and tolerability [evaluated by the result of laboratory safety tests (hematology, chemistry, urinalysis), vital signs, physical examinations, and 12-lead ECG] | Subjects served as their own control for comparison between the effects of Exendin (9-39) and the normal saline vehicle. The trial was terminated after 14 participants enrolled in the study. No data is available for any outcome measures. | Posted | Up to 24 hours post-infusion |
|
|
| Secondary | Mean Plasma Insulin | To assess the effect of Exendin (9-39) on plasma insulin levels, samples were collected at various time points during the infusion [Exendin (9-39) or vehicle] including: at the start of the infusion (T=0) and at 1, 5, and 9 hours post initiation of the infusion. | Subjects served as their own control for comparison between the effects of Exendin (9-39) and the normal saline vehicle. The trial was terminated after 14 participants enrolled in the study. No data is available for any outcome measures. | Posted | Up to 9 hours after the initiation of infusion |
|
|
| Secondary | Mean Plasma Glucose | To assess the effect of Exendin (9-39) on plasma glucose levels, samples were collected at various time points during the infusion [Exendin (9-39) or vehicle] including: at the start of the infusion (T=0) and at 1, 5, and 9 hours post initiation of the infusion. | Subjects served as their own control for comparison between the effects of Exendin (9-39) and the normal saline vehicle. The trial was terminated after 14 participants enrolled in the study. No data is available for any outcome measures. | Posted | Up to 9 hours after the initiation of infusion |
|
|
| Secondary | Mean Betahydroxybutyrate Levels | To assess the effect of Exendin (9-39) on mean betahydroxybutyrate levels, samples were collected at various time points during the infusion [Exendin (9-39) or vehicle] including: at the start of the infusion (T=0) and hourly up to 12-hours post initiation of the infusion. | Subjects served as their own control for comparison between the effects of Exendin (9-39) and the normal saline vehicle. The trial was terminated after 14 participants enrolled in the study. No data is available for any outcome measures. | Posted | Up to 12 hours after the initiation of infusion |
|
|
| 0 |
| 5 |
| 0 |
| 4 |
| 1 |
| 5 |
| EG001 | Exendin (9-39) 0.04 mg/kg/hr | Cohort 2: Participants will be administered 0.04 mg/kg/hr of Exendin (9-39) and vehicle (normal saline), via continuous intravenous infusion, over 9 hours on two separate days in random order, with 3 hours of follow-up after the last dose is administered or until blood glucose is < 70 mg/dL (whichever comes first). | 0 | 2 | 0 | 2 | 2 | 2 |
| EG002 | Exendin (9-39) 0.10 mg/kg/hr | Cohort 3: Participants will be administered 0.10 mg/kg/hr of Exendin (9-39) and vehicle (normal saline), via continuous intravenous infusion, over 6 hours on two separate days in random order, with 3 hours of follow-up after the last dose is administered or until blood glucose is < 70 mg/dL (whichever comes first). | 0 | 2 | 0 | 2 | 2 | 2 |
| EG003 | Exendin (9-39) 0.20 mg/kg/hr | Cohort 4: Participants will be administered 0.20 mg/kg/hr of Exendin (9-39) and vehicle (normal saline), via continuous intravenous infusion, over 9 hours on two separate days in random order, with 3 hours of follow-up after the last dose is administered or until blood glucose is < 70 mg/dL (whichever comes first). | 0 | 4 | 0 | 4 | 4 | 4 |
| EG004 | Vehicle | All participants will be administered normal saline vehicle via continuous intravenous infusion. | 0 | 13 | 0 | 13 | 10 | 13 |
| Hyperglycemia | Endocrine disorders | CTCAE (4.0) | Systematic Assessment |
|
| Hypoglycemia | Endocrine disorders | CTCAE (4.0) | Systematic Assessment |
|
| Abormal Lab Value - AST | Investigations | CTCAE (4.0) | Systematic Assessment |
|
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